Two studies published recently in the Proceedings of the National Academy of Sciences, led by researchers at the Icahn School of Medicine at Mount Sinai, demonstrate how widely used, inexpensive medications to treat osteoporosis, known as bisphosphonates, have the potential to become potent cancer-fighting drugs.
“Our studies, which involved an international team of researchers, reveal a newfound mechanism that may enable physicians to use bisphosphonates to prevent and treat certain types of lung, breast, and colon cancers,” says lead study author Mone Zaidi, MD, PhD, FRCP, Professor of Medicine, and Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai; Director of the Mount Sinai Bone Program; and member, The Tisch Cancer Institute at the Mount Sinai Health System. The scientific team included a number of top investigators in Mount Sinai’s Department of Medicine; the Mount Sinai Bone Program; the Department of Structural and Chemical Biology; and The Tisch Cancer Institute.
Bisphosphonates have been previously associated with slower tumor growth in some patients, but the mechanism was unknown. This new research demonstrates how bisphosphonates reduce the viability of tumor cells by blocking the abnormal growth signals that pass through human epidermal growth factor receptors (HERs). HERs occur on the surfaces of many cell types, regulating cell division and production—processes closely linked to both normal tissue growth and the abnormal growth seen in cancer.
“Many lung, breast, and colon cancers are driven by the HER family of receptors,” says Dr. Zaidi. For example, about 30 percent of non-small cell lung cancers and 90 percent of colon cancers are driven by small genetic changes in HER1, and 25 percent of breast cancers proceed from genetic changes that result in excessive amounts of HER2.
These findings led to a second study that examined the possible applications for bisphosphonates to prevent cancer, fight treatment-resistant tumors, and be used in conjunction with existing treatments. Researchers used the Connectivity Map, a database at The Broad Institute of the Massachusetts Institute of Technology and Harvard University, which analyzes connections among drugs, diseases, and genes to examine which genes become active or inactive after patients receive a given class of drugs.
Once they established the digital link between bisphosphonates and HER receptors, the researchers conducted experiments in cancer cell cultures and in mice. Giving mice bisphosphonates early on prevented HER-driven tumors from forming, and combining bisphosphonates with the cancer drug Tarceva® not only stopped tumor growth but reversed it. In contrast, mice with colon cancer cells that do not signal for growth using HER receptors remained insensitive to bisphosphonate action.
“Having already been approved by the U.S. Food and Drug Administration as effective at preventing bone loss, and having a long track record of safety, bisphosphonates could be quickly applied to cancer if we can confirm in clinical trials that this drug class also reduces cancer growth in people,” says Dr. Zaidi. “It would be much more efficient than starting drug design from scratch.”